In previous studies from our laboratory we have observed that amphetamine releases norepinephrine and dopamine from nerve endings in brain tissue without substantially increasing deamination of the biogenic amine. A model is proposed to explain the releasing action of amphetamine. In this model, the neuronal uptake of amphetamine as well as biogenic amines is carrier mediated. Upon entering the neyron, amphetamine displaces biogenic amines from storage vesicles. The displaced amine binds to the carrier, which is now on the inside of the membrane, and the amine is transported out of the nerve ending. This binding to the carrier protects the displaced amine from deamination by intraneuronal monoamine oxidase. Fenfluramine, a lipid soluble analogue of amphetamine, enters the neuron by passive diffusion and the displaced biogenic amine is metabolized by intraneuronal monoamine oxidase since insufficient carrier is available on the inside of the membrane. This model will be examined by isolating norepinephrine and dopamine enriched synaptosomes, and characterizing the uptake and accumulation of H3- amphetamine and H3-analogues of amphetamine. In the model, sodium ion is cotransported with biogenic amines. Thus sodium ion concentrations inside and outside of the nerve ending will be altered and the resultant changes in the uptake of amphetamine and amphetamine analogues will be studied. Storage vesicles from synaptosomes will be isolated and the ability of amphetamine analogues to displace endogenous norepinephrine and dopamine will be measured. Finally, the efflux of unbound norepinephrine and dopamine produced by amphetamine analogues will be characterized. It is hoped that structural characteristics of amphetamine analogues can be defined so that highly selective releasing agents can be synthesized. This may lead to the development of drugs which can be used either as experimental tools or in brain diseases to specifically activate either dopamine or norepinephrine neurons.